Lung cancer is the leading cause of cancer deaths in both men and women, with the majority of cases being classified as non-small cell lung cancer (NSCLC). Since at time of diagnosis, the majority of lung cancers are already advanced, new strategies are required to target tumor progression and metastasis. Peroxisome proliferator-activated receptor-? (PPAR?), a member of the nuclear hormone receptor superfamily of ligand-activated transcription factors, plays a critical role in adipocyte activation, but has also been implicated in a variety of cancers. During the previous funding period we demonstrated that activation of PPAR? has pleiotropic effects on human NSCLC cells, including promotion of a differentiated phenotype and inhibition of transformed growth and invasiveness. This receptor is the target of thiazolidinediones (TZDs), such as rosiglitazone and pioglitazone. Recent retrospective studies have suggested that these agents specifically reduce the risk of developing lung cancer in patients, making PPAR? an attractive target for treatment of lung cancer. Cancer progression and metastasis require complex interactions between tumor cells and the surrounding tumor microenvironment (TME). We have developed an immunocompetent mouse model for lung cancer cells progression, in which mouse lung cancer cells are injected into the lungs of syngeneic mice. These cells form a primary tumor which metastasizes to the other lobes of the lung, lymph nodes, and distant organs including liver and brain. This model allows manipulation of specific genes in either tumor cells or the TME. Using this model we have unexpectedly shown that in contrast to effects on tumor cells, systemic administration of pioglitazone accelerates tumor progression and promotes metastases. We hypothesize that these disparate effects of PPAR? activation are a result of opposing effects in tumor cells vs. the TME, with activation in tumor cells inhibiting progression and activation in cells of the TME contributing to progression. Our preliminary data indicate that pioglitazone affects the distribution of tumor-associated macrophages and may promote tumor angiogenesis. This project will use in vivo models and in vitro studies to define the contribution of PPAR? in each cell type to tumor progression and metastasis. Three specific aims are proposed. Aim 1 will examine the specific role of PPAR? activation in tumor cells on cancer progression, and define effector pathways in human and murine NSCLC cells. Aim 2 will assess the role of PPAR? in macrophages using a targeted knockout strategy. Studies will use in vitro systems to define cross-talk between cancer cells and macrophages. Aim 3 will employ a similar targeted knockout strategy to assess the role of PPAR? in endothelial cell on tumor progression in the setting of pioglitazone. Since large numbers of patients are treated with TZDs, defining the role of these agents and PPAR? on cancer progression and metastasis is of critical importance. PUBLIC HEALTH RELEVANCE: Studies indicate that activators of PPAR? can inhibit initiation of lung cancer but have conflicting roles on cancer progression and metastasis. This project will define the role for this protein both in tumor cells, macrophages, and endothelial cells using both in vivo and in vitro approaches. Understanding the cell-specific mechanisms whereby PPAR? regulates cancer progression and metastasis is critical in light of the wide-spread use of these agents, and will lead to identification of novel targets and new therapeutic approaches.